Project summary/Abstract Hematopoietic stem cells (HSCs) persist throughout life to generate all blood cells. The microenvironmental niche critically regulates HSCs. The bone marrow is the major organ where adult HSCs reside. Rapid progress has been made regarding the nature and mechanisms of the bone marrow HSC niche. Interestingly, HSCs change tissues and niches during development and in stress. The fetal liver is the major hematopoietic organ where HSCs self-renewal rapidly. Around birth, the liver loses HSC-supporting activity and HSCs egress to seed the bone marrow. The liver can become hematopoietic and support HSCs in extramedullary hematopoiesis (EMH) in stress and some hematologic diseases. However, in contrast to the bone marrow, little is known about the liver HSC niche during development and in stress. Our preliminary data identified stellate cells as a novel key component of the fetal liver HSC niche in vivo. In addition, we have identified a transcriptional factor, Lhx2, that is required for the proper cell fate of stellate cells as the niche cell for HSCs in the fetal liver. The goal of the proposed research is to leverage our knowledge of the fetal liver niche to elucidate the role of Lhx2 in stellate cells during development. We will also study the nature and mechanisms of the adult EMH liver niche. The results of these studies are expected to not only provide new insights on how the liver niche regulates HSCs, but also have the potential to identify mechanisms mediating the generation of new niches to amplify HSCs for clinic use.